1. Field of the Invention
The present invention relates to novel 1-phenylpiperidin-3-one derivatives and pharmaceutically acceptable salts thereof having cysteine protease inhibitory activity, pharmaceutical compositions containing the same as an active ingredient, and processes for the preparation thereof.
2. Description of the Related Art
Cysteine proteases, in particular cathepsins of the papain family, participate in the normal physiological protein degradation, such as connective tissue degradation in animals, including humans. However, elevated levels of these enzymes in the body may cause various diseases. For example, it is reported that calpain protease, one of cysteine proteases, is involved in stroke and neurogdegenerative diseases, such as Alzheimer's disease [G. J. Wells, et. al., Exp. Opin. Ther. Patents, 8(12), 1707 (1998)]; cathepsin B is involved in cancer metastasis [S. Michaud, et. al., Exp. Opin. Ther. Patents, 8(6), 645 (1998)]; and cathepsin L is involved in chronic rheumatoid arthritis and osteoarthritis [H-H Otto & T. Schirmeister, Chem. Rev., 97, 133 (1997)]. International Publication Nos. WO 00/49007, WO 00/49008 and 00/48992 disclose that cathepsin S is involved in chronic obstructive pulmonary disease (COPD).
As cysteine proteases other than the papain family, caspase proteases are also known to be involved in inflammatory diseases such as osteoarthritis [D. D. Fairlie et al, J. Med. Chem. 43(3), 305 (2000)] and Rhinovirus 3C protease is involved in influenza [Q. M. Wang, Exp. Opin. Ther. Patents, 8(9), 151 (1998)].
Moreover, it is known that cathepsin K is distributed selectively in osteoblasts associated with bone resorption in a bone remodeling process and plays an important role in degradation of organic matter in bones. Accordingly, various attempts have been made to develop a novel agent for treating osteoporosis by inhibiting such proteases [W. W. Smith, et. al., Exp. Opin. Ther. Patents, 9(6), 683 (1999); W. Kim, et. al., Exp. Opin. Ther. Patent, 12(3), 419 (2002)].
For example, it has been reported that vinylsulfone group-containing peptidomimetic compounds irreversibly inhibit cysteine proteases including cathepsin K [J. T. Palmer, et. al., J. Med. Chem., 38, 3139 (1995); W. W. Roush, et. al., J. Am. Chem. Soc., 120, 10994 (1998)]. Various peptidyl or peptidomimetic compounds having 1,3-diamino-1,3-propan-2-one as a main chain have been also reported to inhibit cysteine proteases including cathepsin K [D. S. Yamashita, et. al., J. Am. Chem. Soc., 119, 11351 (1997); S. K. Thompson, et. al., Proc. Nacl. Acad. Sci., 94, 14249(1997); WO 98/08802; WO 98/48799; WO 98/49152; WO 98/50342; WO 98/50534; and WO 99/11637]. Peptidyl aldehyde (Japanese Patent Publication Nos. 8/092193, 8/151394 and 10/147,564, and WO 98/25899) and peptidyl epoxysucinamides (WO 98/47887) are proposed as irreversible cysteine protease inhibitors. WO 98/50533 proposes peptidyl 3-keto-heterocyclic derivatives, as a cathepsin K inhibitor. Further, it has been also reported that peptidyl α-ketoamides (EP 10085920); peptidyl phenylethylamines (WO 00/48993); peptidyl cycloketones (WO98/05336); and peptidyl azepines (WO 00/38687 and WO 01/34565) inhibit cysteine proteases, including cathepsin K.
However, those peptidyl compounds as known in the art readily subject to attack of proteolytic enzymes in the body, and therefore, it is difficult to develop drugs based on peptidyl compounds for treating diseases such as osteoporosis [Rasnick, D. Perspect. Drug Discov. Design, 6, 47(1996); M. Sato, et. al., J. Med. Chem., 42, 3(1999); W. W. Smith, et. al., Exp. Opin. Ther. Patents, 9(6), 683 (1999)]. Further, structural similarities in active sites of cathepsins B and L; and cathepsins K and S make it difficult to develop selective cysteine protease inhibitors each having a satisfactory selectivity to respective cathepsins, such as cathepsin B, L, K, and S [W. Kim, et. al., Exp. Opin. Ther. Patents, 12(3), 419 (2002)]. Besides, there has been a demand in the art to develop cysteine protease inhibitors having sufficient bioavailability and physicochemical stability enabling practical pharmacokinetic evaluations in oral administration.